PROJECT ABSTRACT With an estimated 35.5 million people living with HIV worldwide and 2.3 million people newly infected with HIV in 2012, new cost-effective HIV prevention methods are needed. Co-infections play an important role in the HIV epidemic by increasing susceptibility to HIV and increasing transmission. Schistosomiasis, a disease caused by a parasitic flatworm, has a prevalence greater than 20% in many of the sub-Saharan African countries worst impacted by HIV. Epidemiological and molecular data suggest that schistosomiasis is associated with HIV acquisition and transmission, but existing studies had small samples sizes, were cross-sectional in design, and failed to adjust for potential confounders. These limitations in the existing literature have kept the observed association from being widely accepted in the HIV prevention research community. Our proposal addresses this gap in our understanding of the interaction between HIV-1 and the common co-infection schistosomiasis. We will use biological samples and data collected from four longitudinal studies of HIV transmission conducted in schistosomiasis-endemic areas of Kenya and Uganda to address whether schistosomiasis increases the risk of HIV-1 acquisition, transmission or disease progression and estimate the population attributable fraction of HIV incident cases associated with schistosome infection. We will test schistosome infection status prior to HIV acquisition, determining both prevalent and acute infection, and measure HIV viral load in genital secretions and plasma. In aim 1, we will estimate the association between schistosome infection and HIV-1 acquisition. We will test our hypothesis that schistosomiasis is associated with an increased incidence risk of HIV acquisition. In aim 2, we will evaluate the impact of schistosome co-infection on HIV infectiousness. We will test two hypotheses: 1) that schistosomiasis is associated with increased levels of HIV-1 RNA in the genital tract of women and men, a marker of HIV transmission risk and 2) that schistosomiasis is associated with an increased risk of HIV transmission to primary sexual partners. In aim 3, we will evaluate whether schistosome co-infection is associated with more rapid disease progression among individuals newly infected with HIV-1. We will test our hypothesis that schistosomiasis is associated with increased levels of HIV-1 RNA in plasma collected 4-12 months after HIV-1 acquisition, which is a measure of increased HIV-1 viral replication and more advanced HIV-1 disease. Schistosomiasis can be safely treated with a single dose of praziquantel at an estimated cost of US $0.20-0.30 per treatment. If our study finds a strong association between schistosomiasis and HIV transmission, acquisition, or diseases progression, an additional benefit of mass treatment of schistosomiasis would be safe and cost-effective prevention of HIV.